Antidepressant method and composition

ABSTRACT

The antidepressant action of tricyclic antidepressants is enhanced by concurrent administration of thyroid hormone. A composition for treating depression comprises a tricyclic antidepressant and a thyroid hormone in pharmaceutically effective amounts admixed with a pharmaceutical carrier.

United States Patent [151 3,689,669 1 Sept. 5, 1972 Prange, Jr. et al.

ANTIDEPRESSANT METHOD AND COMPOSITION Inventors: Arthur J. Prange, Jr.,Chapel Hill; Ian C. Wilson; Morris A. Lipton,

both of Raleigh, all of N.C.

Assignee: The University of North Carolina,

Chapel Hill, N.C.

Filed: Oct. 9, 1970 Appl. No.: 79,704

Related US. Application Data Division of Ser. No. 813,294, April 3,1969, Pat. No. 3,621,096.

US. Cl ..424/319, 424/330 Int. Cl. ..A61k 27/00 Field of Search ..424/319, 330

References Cited OTHER PUBLICATIONS Merck Index, 7th Ed. (1960) p. 1066.Grollman, Pharmacology & Therapeutics 6th Ed. (1965). pp. 274, 275

Primary Examiner-Stanley J. Friedman Attorney-Wenderoth, Lind & PonackABSTRACT 8 Claims, No Drawings l ANTIDEPRESSANT METHOD AND COMPOSITIONThis application is a divisional application of application Ser. No.813,294, filed Apr. 3, 1969, now US. Pat. No. 3,621,096.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

The present invention is concerned with mental depression and thetreatment thereof. More specifically there is provided a novel methodfor the treatment of mental depression using a combination ofpharmaceutically effective materials. The invention also provides acomposition for use in the treatment of depression.

A tremendous amount of research effort has been invested in recent yearsin the study of mental depression and to methods for its treatment. Muchof this eflort has gone into the discovery of the biological causes ofdepression and to chemical substances which might be utilized in asystem of therapy related to these biological causes. While a largenumber of drugs are now available which will ameliorate depression andwhile a great deal of investigation has been conducted with these drugs,to a great extent the knowledge concerning biological causes ofdepression remains incomplete. Also, the drugs presently availablesuffer from various disadvantages and are not optimum. In this latterrespect there can be mentioned relatively slow onset of action. This isespecially critical since the omnipresent danger of suicide indepression makes speed of treatment a prime consideration. It hasrecently been pointed out that the conquest of general paresis has leftsuicide virtually the sole cause of death from mental illness.

The present invention provides a method for the treatment of depressionconstituting an advance over previously employed methods. According tothis method a combination of pharmaceutically effective substances isadministered to a patient sufiering from depression. The substancesadministered are (l) a tricyclic antidepressant drug and (2) a thyroidhormone.

The tricyclic antidepressant drugs are well known toe the art and areillustrated by those such as imipramine (-(3-dimethylaminopropyl)-10,1ldihydro-SI-I-dibenz [b,f]azepine hydrochloride), desmethylimipramine(5-(3-methylaminopropyl)- 10,1 l-dihydro-5H-[b,f]azepine,protriptyline(5-( 3- methylaminopropyl)-dibenzo a,d]cyclohepta-[ 1,4,6]triene), amitriptyline(5-(3-dirnethylaminopropylidene)-dibenzo[a,d]cyclohepta[l,4]diene), andnortriptyline-(5-(3-methylaminopropylidene)-dibenzo[a,d]cyclohepta[]-diene), and the like. As indicated these tricyclicantidepressants are well known to the art skilled and have beenpreviously employed in the treatment of mental depression. Preferredamong these tricyclics for purposes of this invention are imipramine andamitriptyline. For purposes of this invention the tricyclic drugs may beemployed as the base or as a salt with an organic or inorganic acid.

The thyroid hormone which is employed may be of natural or syntheticorigin. Such materials are known to the art and are conventionally usedin treating hypothyroidism. Illustrative of the thyroid hormones are L-triiodothyronine (l3-[4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]alanine) and L-tetraiodothyronine (B-[4- 2hydroxy-3,5-diiodophenoxy)-3,S-diiodophenyl] alanine). These materialsare also referred to as T3 and T4 respectively. The sodium salts of thematerials are available commercially.

In carrying out the method of the invention,'

depressed patients are given the combination of substances atpharmaceutically effective dosage levels. The substances areadministered in the form of a single dosage unit in which the activeingredients are combined with a suitable carrier; or they may be givenin separate dosage units in which the active materials are individuallycombined with a suitable carrier. When administered separately, theadministration may be simultaneous or at selected time intervals.

The administration is preferably peroral and the carrier or carriers areselected with this in mind. While this is the case, other modes ofadministration of both substances as well as mixed modes with theindividual materials is not precluded.

The dosage levels of the materials will vary with the particularmaterial being used and the severity of the condition of the patientbeing treated. The tricyclic antidepressant is used in amounts rangingfrom those conventionally employed in treating depression to amountssomewhat lower. In general the amount will be from about to about 250 mgper day, and more specifically in amounts of about to 200 mg per day.Illustrative of a dosage in accordance with this invention is mg oftricyclic antidepressant in the form of two 25 mg capsules, tid.

The thyroid hormone is administered at levels sufficient to enhance theactivity of the tricyclic antidepressant which is employed. This amountwill vary with the patient and the severity of the condition.Illustrative of the invention is T3 or T4 administered in a daily dosageof 15 to to 50 pg, with a dosage of about 20 to 30 p.g being preferred.

The pharmaceutical compositions of the invention are prepared byutilizing the active ingredients in association with the pharmaceuticalcarriers conventionally employed with such materials.

The compositions of the present invention are in general contemplatedfor administration orally to achieve an antidepressant effect. This maybe in any of the dosage forms such as tablets, capsules, powders,suspensions, solutions, syrups and the like, including sustained releasepreparations. The term dosage form as used in this specification and theclaims refer to physically discrete units to be administered in singleor multiple dosage to animals, each unit containing a predeterminedquantity of active material in association with the required diluent,carrier or vehicle. The quantity of active material is that calculatedto produce the desired therapeutic effect upon administration of one ormore of such units.

Powders are prepared by comminuting the active substances to a suitablyfine size and mixing with a similarly comminuted diluent pharmaceuticalcarrier such as an edible carbohydrate material as for example, starch.Sweetening, flavoring, preservative, dispersing and coloring agents canalso be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. A lubricant such as talc, magnesiumstearate and calcium stearate can be added to the powder mixture as anadjuvant before the filling operation; a glidant such as colloidalsilica may be added to improve flow properties; a disintegrating orsolubilizing agent may be added to improve theavailability of themedicament when the capsule is ingested.

Tablets are made by preparing a powder mixture, granulating or slugging,adding a lubricant and disintegrant and pressing into tablets. A powdermixture is prepared by mixing the active substance, suitably comminuted,with a diluent or base such as starch, sucrose, kaolin, dicalciumphosphate and the like. The powder mixture can be granulated by wettingwith a binder such as syrup, starch paste, acacia mucilage or solutionsof cellulosic or polymeric .materials and forcing through a screen. Asan alternative to granulating, the powder mixture can be run through thetablet machine and the resulting imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The libricated mixture is then compressedinto tablets. The medicaments can also be combined with free flowinginert carriers and compressed into tablets directly without goingthrough the granulating or slugging steps. A protective coatingconsisting of a sealing coat of shellac, a coating of sugar or polymericmaterial and a polish coating of wax can be provided. Dyestuffs can beadded to these coatings to distinguish different unit dosages.

Oral fluids such as syrups and elixirs can be prepared in unit dosageform so that a given quantity, e.g., a teaspoonful, contains apredetermined amount of the compound. Syrups can be prepared bydissolving the compound in a suitably flavored aqueous sucrose solutionwhile elixirs are prepared through the use of a nontoxic alcoholicvehicle. Suspensions can be formulated by dispersing the medicaments ina non-toxic vehicle in which it is insoluble.

One important embodiment of the present invention, particularly forpreparing solid pharmaceutical formulations, is the pharmaceuticallyacceptable non-toxic acid addition salts of the tricyclic drugs. Suchpharmaceutically acceptable non-toxic salts include those derived fromboth organic and inorganic acids such as, without limitation,hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic,acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric,embonic, enenthic and the like acids.

While the present invention contemplates, primarily, peroraladministration, other modes are certainly not excluded. Ampoules forparenteral application can be prepared and preferably contain watersoluble salts of the active substances and possible buffer substances inaqueous solution.

In liquid compositions, whether designed for peroral or parenteraladministration in which the active substances are combined, care must betaken to insure stability of the active materials.

In cases where the active materials are to be administered separately,individual compositions are prepared in the manner indicated above.These individual compositions can then be administered as such orcombined into a single dosage unit while maintaining the separateidentity, as for example in a multi-layer tablet or singlecapsulecontaining both components in a plurality of discrete particles.

The following exemplary data are set forth in order to illustrate theinvention and should not be taken to be exhaustive thereof. It will beapparent to persons skilled in the art that various modifications can bemade without departing from the scope of the invention.

A group of primarily depressed patients admitted to a state mentalinstitution were employed in this study. After exclusion of thyroid andcardiovascular disease detectable by usual historial, physical andlaboratory examination, each depressed patient was assigned to one oftwo treatment plans according to a prearranged, randomized schedule. Allinitial differences between the two treatment groups were statisticallyinsignificant (p. 1.). In this regard see Table I. All patients werefree of psychotropic drugs for at least one week before entering thestudy. The patients were weighed and their height and transverse chestdiameter measured.

On the day before beginning drug treatment each patient received thefollowing: Self-Rating Scale for Depression (SDS) [Zung, W.W.K: ASelf-Rating Depression Scale, Arch. Gen. Psychiat., 12:63, 1965];Hamilton Rating Scale for Depression (HRS) [Hamilton, M: A Rating Scalefor Depression, J. Neurol. Neurosurg. Psychiat., 23:56-62, 1960];Inpatient Multidimensional Psychiatric Scale (IMPS) [Lorr, M., Kleet,C.J., and McNair, DM: Syndromes of Psychosis, MacMillan and Company, NewYork, 1963]. These SDS and HRS measurements were repeated thrice weeklythroughout the course of the study. One investigator, experienced withthe measures but not informed of medication and having no otherconnection with the study performed all ratings.

On day l and thereafter all patients received mg of imipramine in theform of two 25 mg capsules, tid. Beginning on day 5, half the patients,according to schedule, in addition received daily one capsule containingT3 25 pg, and half received daily a capsule containing inert placebo(P). All 3 capsules (imipramine, T3 and P) were identical in appearance.During the course of the study no other drugs were administered. Allpatients were housed in the same admission ward of the hospital.Psychotherapy, aside from that implied by routine care, was not used.

RESULTS The first dose of T3 or P was given early on day 5. Several T3patients, but no P patients, were remarkably improved 8 hours later whenpsychometric testing was performed. The difference between groupsincreased steadily and became statistically significant on HRS on day 9and on SDS on day 12.

As a criterion of definitive outcome, there was chosen the time requiredfor a patient to achieve (and subsequently not to exceed) an HRS scoreof 8, which roughly corresponds to his being ready for discharge onclinical grounds. T3 patients attained this criteria in 17.4 days (S.D$9.7); P patients in 24.8 days (i 6.2). These differences arestatistically significant (P 05, Mann-Witney U test).

Four P patients were declared clinical failures in the 5th or 6th weekafter beginning treatment. Three were given T3, 25 pg daily and allshowed quick remission within one week. The fourth responded well,though slowly, to electric shock treatment. No T3 patients were finallydeclared failures, although 3 had not obtained full remission by day 28.Three other T3 patients obtained full and lasting remission before day9. Two of these and one other T3 patient were discharged between day 19and day 28, having demanded discharge. Six months after conclusion ofthe study two P patients had been readmitted for depression but no T3patients, although they received no T3 after leaving the hospital.

Suicidal tendencies were greatly diminished by the use of T3. (HRSSubscale).

In order to determine whether the conjoint use of T3 might producecertain symptoms while removing others, a drug toxicity inventory wasutilized. This was in accordance with Sandifer, M.G. Wilson, l.C., and

BLE I minuted mixture of 500 gms. imipramine, 0.1 gms. of

What is claimed is:

l. A method for the treatment of mentally depressed patients whichcomprises perorally administering to a patient suffering from mentaldepression from about 75 mg. to about 250 mg. daily of a tricyclicantidepressant selected from the group consisting of nortriptyline,amitriptyline and protriptyline and from about 15 ug. to about 50 1.1g.daily of a thyroid hormone selected from the group consisting ofL-triiodothyronine and L- tetraiodothyronine.

2. A method as in claim 1 wherein the thyroid hormone isL-triiodothyronine.

TA Initial characteristics of treatment groups Biological measures IMPSsubseales relevant to depression Age Men Women Excitement HostilityIntrapunitive Retardation Imi rarnine lus lacebo 45.4 (ill-4) 1 9 1.0($1.3) 6.3 ($5.0) 44.0 ($5.6) 35.3 ($4.8 Imigraminc 5111s %3 41.7(:l:10-6) 3 7 1.9 ($23) 7.3 (314.9) 43.6 (5:5.0) 35.9 ($6.1

" Means and standard deviations.

The study results previously set forth make it clear that the use ofthyroid hormone in conjunction with the tricyclic antidepressantenhances the activity of the antidepressant. The specific biologicalmechanism by which the thyroid hormone acts to enhance theantidepressant activity is not entirely clear. It is clear, however,that the conjoint use of the materials is superior to the use of theantidepressant alone.

Results substantially similar to those set forth above are obtained whenutilizing a composition in which imipramine and L-triiodithyronine arecombined in a single dosage unit with a solid perorally acceptablepharmaceutical carrier.

The following provides an illustrative example of the preperation of aperoral dosage unit of the present invention.

CAPSULES 11' t l t sheaths. The resultin eroral dosa e iififi mg. ofimipramine ar id 10 #g. of

triiodothyronine and is administered to patients suffering from mentaldepression in accordance with this invention.

TABLETS Tablets are prepared by carefully admixing a com- 3. A method asin claim 1 wherein the tricyclic antidepressant is amitriptyline.

4. A method as in claim 1 wherein the tricyclic antidepressant isamitriptyline and the thyroid hormone is L-tetraiodothyronine.

5. A method as in claim 4 wherein the thyroid hormone isL-triiodothyronine.

6. A peroral composition for the treatment of mental depression whichcomprises an antidepressant effective amount of a mixture of a tricyclicantidepressant selected from the group consisting of nortriptyline,amitriptyline and protriptyline and a thyroid hormone selected from thegroup consisting of L- triiodothyronine and L-tetraiodothyronine inadmixture with a perorally acceptable pharmaceutical carrier, the ratioof active constituents being about 250 mg. tricyclic antidepressant toabout 15 50 mg. hormone.

7. A composition as in claim 6 in peroral dosage unit form wherein thetricyclic antidepressant is present in an amount sufficient to give adaily dosage of from about 75 to 250 mg. when administered according toa desired daily dosage regimen and the thyroid hormone is present in anamount sufficient to give a daily dosage of from 15 to 50 mg. whenadministered according to a desired daily dosage regimen.

8. A composition in dosage unit form for use in treating mentaldepression which comprises from about 20 to about 50 mg ofamitriptyline, about 5 to about 10 ug of L-tetraiodothyronine and asolid perorally acceptable pharmaceutical carrier.

2. A method as in claim 1 wherein the thyroid hormone isL-triiodothyronine.
 3. A method as in claim 1 wherein the tricyclicantidepressant is amitriptyline.
 4. A method as in claim 1 wherein thetricyclic antidepressant is amitriptyline and the thyroid hormone isL-tetraiodothyronine.
 5. A method as in claim 4 wherein the thyroidhormone is L-triiodothyronine.
 6. A peroral composition for thetreatment of mental depression which comprises an antidepressanteffective amount of a mixture of a tricyclic antidepressant selectedfrom the group consisting of nortriptyline, amitriptyline andprotriptyline and a thyroid hormone selected from the group consistingof L-triiodothyronine and L-tetraiodothyronine in admixture with aperorally acceptable pharmaceutical carrier, the ratio of activeconstituents being about 75 - 250 mg. tricyclic antidepressant to about15 - 50 mg. hormone.
 7. A composition as in claim 6 in peroral dosageunit form wherein the tricyclic antidepressant is present in an amountsufficient to give a daily dosage of from about 75 to 250 mg. whenadministered according to a desired daily dosage regimen and the thyroidhormone is present in an amount sufficient to give a daily dosage offrom 15 to 50 mg. when administered according to a desired daily dosageregimen.
 8. A composition in dosagE unit form for use in treating mentaldepression which comprises from about 20 to about 50 mg ofamitriptyline, about 5 to about 10 Mu g of L-tetraiodothyronine and asolid perorally acceptable pharmaceutical carrier.